Generation of pure GABAergic neurons by transcription factor programming

Nan Yang, Soham Chanda, Samuele Marro, Yi Han Ng, Justyna A. Janas, Daniel Haag, Cheen Euong Ang, Yunshuo Tang, Quetzal Flores, Moritz Mall, Orly Wapinski, Mavis Li, Henrik Ahlenius, John L. Rubenstein, Howard Y. Chang, Arturo Alvarez Buylla, Thomas C. Südhof, Marius Wernig

Research output: Contribution to journalArticlepeer-review

231 Scopus citations

Abstract

Approaches to differentiating pluripotent stem cells (PSCs) into neurons currently face two major challenges-(i) generated cells are immature, with limited functional properties; and (ii) cultures exhibit heterogeneous neuronal subtypes and maturation stages. Using lineage-determining transcription factors, we previously developed a single-step method to generate glutamatergic neurons from human PSCs. Here, we show that transient expression of the transcription factors Ascl1 and Dlx2 (AD) induces the generation of exclusively GABAergic neurons from human PSCs with a high degree of synaptic maturation. These AD-induced neuronal (iN) cells represent largely nonoverlapping populations of GABAergic neurons that express various subtype-specific markers. We further used AD-iN cells to establish that human collybistin, the loss of gene function of which causes severe encephalopathy, is required for inhibitory synaptic function. The generation of defined populations of functionally mature human GABAergic neurons represents an important step toward enabling the study of diseases affecting inhibitory synaptic transmission.

Original languageEnglish
Pages (from-to)621-628
Number of pages8
JournalNature Methods
Volume14
Issue number6
DOIs
StatePublished - May 30 2017

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